N-phenethyl-beta-alanine derivatives



Patented Dec. 19, 1950 UNITED STATES PATENT OFFICE N-PHEN ETHYL -BETA-ALANIN E DERIVATIVE S York No Drawing. Application June 21, 1947, Serial No. 756,335

3 Claims.

The present application is a continuation-inpart of our co-pending applications Serial Numbers 528,448 and 528,449, both filed March 28, 1944, and both now abandoned.

Our invention relates to certain N-phenethylbeta-alanine derivatives and is based on the discovery that certain N-phenethyl-beta-alanine esters and alkylolamides have valuable physiological properties, especially in stimulating uterine smooth muscle Without acting as general pressor drugs, combined with low toxicities.

One group of compounds of this type showing considerable potencies are the compounds in which the beta-carbon of the phenethyl group (counting from the nitrogen atom) is substituted with hydroxyl, with or without methyl or alkoxy substituents in the phenyl ring, these substances forming the subject matter or" our simultaneously filed companion application Serial No. 756,335, filed June 21, 1947, and now Patent No. 2,503,652.

Another group of active substances consists of the N-phenethyl-beta-alanine esters in which the phenyl ring is connected to the nitrogen by a pure hydrocarbon chain and the phenyl ring has two methoxy groups attached thereto.

These compounds which form the subject matter of the present invention can be represented by the general formula C1130 OH; (I?

in which R is a straight chain alkoxy containing from 1 to 5 carbon atoms.

The compounds according to the invention as represented in the general formula above, are tertiary amines which may be combined with various acids to form salts for convenience in handling and stability. The nature of the acids forming these acid salts of the tertiary amines is ordinarily of no importance for the physiological properties but may influence the ease of crystallization or purification. Thus in most cases salts of hydrochloric acid are at least as satisfactory as salts of other acids, but some compounds have been isolated more readily as sulfates, phosphates, tartrates, malates, succin- CHaO ates, hydrobromides, etc. Such variations in the salts employed for the manipulations of organic bases are common and, when useful, obvious, and we neither consider any part of our invention to consist therein nor do We conceive that any absence of mention of the use of such common acids shall be held to limit the inven tion. The claims appended hereto are intended to cover the tertiary bases as well as their acid salts.

The physiological properties of the type displayed by the present family of compounds are not shown by N-benzyl or N-substituted benzyl beta-alanine esters or by variously substituted N -phenethy1 glycine esters or N-phenethyl alphaalanine esters. It is thus apparent that the chain of two carbon atoms between the aromatic ring and the basic nitrogen is essential as is also the chain of two carbon atoms between the nitrogen atom and the carbalkoxyl group.

The new compounds according to the invention may conveniently be prepared by several methods, the starting materials being suitably substituted phenalkyl secondary amines, especially those belonging to and related to the socalled pressor bases. These phenalkylamines are reacted either with esters of suitably selected halogenoacids or, preferably with esters of alphabeta-unsaturated acids such as acrylic acid esters.

The tertiary bases according to the general formula are obtained by either of two general methods. In the first of these, the appropriate phenyl alkanolamine, in relation to the preceding general formula, to be represented as is reacted with a beta-halogeno, usually a betabromopropionic ester. This reaction is not unsatisfactory but since a separation of basic substances is necessary and since only half (at most) of the more valuable intermediate can be utilized we prefer a second line of synthesis.

According to this second method the amine is treated with an excess of an ester of acrylic acid, usually methyl acrylate, the reaction being in the sense of the equation:

The product so obtained is a. tertiary base. The bases so obtained can be converted into the desired salts by methods generally known in the art. The nature of the acid employed is ordinarily of minor importance for the physiological action but certain salts have physical propertiesmaking them more or less advantageous for purification. In most cases the chlorides have been used and they are generally preferred but other salts, such as the bromides, iodides, phosphates, sulfates, oxalates, tartrates, succinates, malates, etc., have at times proved convenient.

The amines used in the preparation of the compounds according to the invention are well known in the art and their preparation does not form any part of the present invention.

Although other esters of acrylic acid than the methyl ester may be used in the second line of synthesis, methyl acrylate is the most readily available and has generally been employed. The conversion of the beta-alanine methyl esters into higher alkyl esters (corresponding to variations in R) can be accomplished conveniently by heating the methyl ester in a large excess of the appropriate higher alcohol containing anhydrous hydrogen chloride under a fractionating column. During several hours heating, distillate is allowed to pass over gradually and an ester exchange takes place in the solution, the alkyl group of the higher alcohol replacing the methyl group in the ester.

A typical line of synthesis of compounds according to the present invention is presented below:

Decker The following specific examples may serve to illustrate, without limiting, the invention.

EXAMPLE 1 N methyZ-N-(2,3 dimethoryphenethyb betaalanine ethyl ester acid oxalate Eleven g. of 2,3-dimethoxyphenethyl methylamine was reacted in absolute ethanol with 11 g. of ethyl-beta-bromopr0pionate. There was considerable heat of reaction. After standing over-night most of the alcohol was boiled off, and the residue was acidified with hydrochloric acid. An ethereal extract of the solution at this stage contained practically no material boiling over 90 C. The basic material was liberated from aqueous solution by addition of alkali, taken into ether, dried over KzCOa and treated with cc. of acetic anhydride. Basic material was again extracted with aqueous acid and the base again liberated. The hydrochloride could not be induced to crystallize so the base was liberated by alkali, taken into ether and dried over potassium carbonate. After filtration from the desiccant, the solution was poured int cabsolute ether containing a large excess of anhydrous oxalic acid. The precipitated solid was recrystallized from acetone and then melted at l38.5 C.

EXAMPLE 2 N methyZ-N-(ZA dimethozcyphenethyl) beta.-

alam'ne ethyl ester acid oxalate This substance was prepared from 2,4-dimethod CHgO CHzCHzNHCH:

CH2=CHOOOCH3 I? O (3H3 2 CH3OOOH2OH2-N-CH2CH2O o OCH: 5 O 0%) Cz a 8 H01 (111a c1130 cm-om-N-cmomo 0 001m on olmon HCl The following list of substances prepared by syntheses of this type is intended to exemplify the invention without limiting it except as expressed in the general formula:

1. N methyl N (2,3 dimethoxyphenethyl) beta-alanine ethyl ester acid oxalate. 2. N methyl N (2,4 dimethoxyphenethyl) beta-alanine ethyl ester acid oxalate. N methyl N (2,5 dimethoxyphenethyl) beta-alanine methyl ester hydrochloride. 4. N methyl N (2,5 dimethoxyphenethyl) beta-alanine ethyl ester hydrochloride. 5. N methyl N (3,4 dimethoxyphenethyl)- beta-alanine methyl ester hydrochloride. 6. N methyl N (3,4 dimethoxyphenethyl) beta-alanine ethyl ester hydrochloride. 7. N methyl N (3,4 dimethoxyphenethyl) beta-alanine ethyl ester hydrobromide. N methyl N (3,4 dimethoxyphenethyl) beta-alanine-n-butyl ester hydrochloride. 9. N methyl N (3,4 dimethoxyphenethyl) beta-alanine-n-amyl ester acid oxalate,

methoxyphenethyl methylamine and ethyl-betabromopropionate by the method of Example 1 (the hydrochloride being again uncrystallizable) The acid oxalate crystallizes from acetone in rosettes of needles and melts at 120.5-l2l C.

EXAMPLE 3 N-methyl N (2,5-dimethoxyphenethyl) betaalcmine methyl ester hydrochloride EXAMPLE 4 N-methyl N (2,5-dimethoxyphenethyl) betaalanz'ne ethyl ester hydrochloride Thirty-nine g. (0.2 mole) of 2,5-dimethoxyphenethyl methylamine were reacted in absolute alcohol with 36 g. (0.2 mole) of ethyl-beta-bromopropionate by the method according to Example 1. After drying in ethereal solution over K2003 the basic product was in this case precipitated by adding an excess of absolute alcoholic HCl and the resulting hydrochloride was purified by recrystallization from alcohol-acetone-ether mixtures. The compound forms glossy platelets, M. P. 105.5-106.5 C.

EXAMPLE 5 N-methyl N (3,4-climethoxyphenethyl) betaalanine methyl ester hydrochloride Nineteen and five tenths g. (0.1 mole) of N- methyl homoveratrylamine was dissolved in benzene. To it was added 13 g. (0.15 mole) of methyl acrylate. The solution was allowed to stand over-night and then refluxed about an hour. On cooling a small amount (2-5 cc.) of phenyl isocyanate was added in portions until the intense odor of this reagent persisted for -15 minutes. By this procedure any secondary amine still present was converted to a non-basic substance (the corresponding phenyl urea). Excess phenyl isocyanate was destroyed by adding methyl alcohol. The desired tertiary base was extracted with dilute hydrochloric acid, and then liberated by alkali, taken into ether, dried over K2003 and precipitated with methanolic HCl. The hydrochloride was crystallized from methanol-acetoneether mixture and melted at 120-122 C. The treatment with phenyl isocyanate and the subsequent extractions are not necessary and have at times been omitted without harm.

According to a variation, instead of liberating the tertiary base from the aqueous acid solution, the latter was evaporated to dryness (the last stage in vacuo). In this case, the material was obtained as the hydrochloride of the acid. This could be re-esterified with other alcohols thus giving propyl, n-butyl, n-amyl esters, etc.

EXAMPLE 6 N-methyl N (3,4-dimethoxyphenethyl) betaa'lanine ethyl ester hydrochloride This compound was prepared from N-methyl homoveratrylamine and ethyl beta-bromopropionate by the method of Example 4. The product forms slender needle-prisms melting at 139- 139.5" C.

The same substance was also prepared from N- methyl homoveratrylamine and ethyl acrylate following the method of Example 5 and from the methyl ester (of Example 5) in the following fashion:

Seven g. of the methyl ester chloride prepared according to Example 5 was dissolved in cc. of absolute ethanol and 20 grams of ethanolic hydrogen chloride (35% by Weight) was added. The solution was refluxed fifteen hours and evaporated to small volume. Ethyl acetate and absolute ether were added and the solution was cooled. There crystallized 7 g. of a solid identical with that formed in the previous procedure.

EXAMPLE '7 N-methyl N (3,4-dimethoxyphenethyl) betaa'lam'ne ethyl ester hydrobromide Fifteen grams of N-methyl homoveratrylamine was dissolved in 35 cc. of absolute ethanol and 12.4 grams of ethyl-beta-bromopropionate was in which R is a straight alkoxy chain containing from 1 to 5 carbon atoms and salts thereof.

2. N methyl N (ZA-dimethoxyphenethyl) beta-alanine ethyl ester acid oxalate.

3. N methyl -N (3,4-dimethoxyphenethyl) beta-alanine ethyl ester hydrochloride.

RICHARD BALTZLY.

ARTHUR P. PHILLIPS.

LOWELL O. RANDALL.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Peyer Jan. 21, 1941 OTHER REFERENCES J. R. Thayer et al.: Chem. Abstracts, vol. 22, page 81 (1928).

Number 

1. A NEW COMPOSITION OF MATTER SELECTED FROM THE GROUP CONSISTING OF THE COMPOUNDS HAVING THE FOLLOWING GENERAL FORMULA 